[68Ga]Pentixafor PET/CT for staging and prognostic assessment of newly diagnosed multiple myeloma: comparison to [18F]FDG PET/CT.

PURPOSE: To evaluate the prognostic performance of [68Ga]Pentixafor PET/CT at baseline for staging of patients with newly diagnosed multiple myeloma (MM) and to compare it with [18F]FDG PET/CT and the Revised-International Staging System (R-ISS). METHODS: Patients who underwent [68Ga]Pentixafor and [18F]FDG PET/CT imaging were retrospectively included. Patient staging was performed according to the Durie-Salmon PLUS staging system based on [68Ga]Pentixafor PET/CT and [18F]FDG PET/CT images, and the R-ISS. Progression-free survival (PFS) at patient follow-up was estimated using the Kaplan-Meier estimator and compared using the log-rank test. Area under the receiver operating characteristic curve (AUC) was calculated to assess predictive performance. RESULTS: Fifty-five MM patients were evaluated. Compared with [18F]FDG PET, [68Ga]Pentixafor PET detected 25 patients as the same stage, while 26 patients were upstaged and 4 patients were downstaged (P = 0.001). After considering the low-dose CT data, there was no statistically significant difference in the number of patients classified in each stage using [68Ga]Pentixafor PET/CT and [18F]FDG PET/CT (P = 0.091). [68Ga]Pentixafor PET/CT-based staging discriminated PFS outcomes in patients with different disease stages (stage I vs. stage II, stage I vs. stage III, and stage II vs. stage III; all P < 0.05), whereas for [18F]FDG PET/CT, there was only a difference in median PFS between stage I and III (P = 0.021). When staged by R-ISS, the median PFS for stage III was significantly lower than that for stage I and II (P = 0.008 and 0.035, respectively). When predicting 2-year PFS based on staging, the AUC of [68Ga]Pentixafor PET/CT was significantly higher than that of [68Ga]Pentixafor PET (0.923 vs. 0.821, P = 0.002), [18F]FDG PET (0.923 vs. 0.752 P = 0.002), and R-ISS (0.923 vs. 0.776, P = 0.005). CONCLUSIONS: [68Ga]Pentixafor PET/CT-based staging possesses substantial potential to predict disease progression in newly diagnosed MM patients.

Functional nodules in primary aldosteronism: identification of CXCR4 expression with 68Ga-pentixafor PET/CT.

OBJECTIVES: We analyzed the diagnostic efficiency of 68Ga-pentixafor PET/CT for functional nodules in primary aldosteronism (PA). Furthermore, we compared the correlation of CXCR4 expression with aldosterone synthase (CYP11B2) expression and PET/CT uptake in these patients. METHODS: We prospectively assessed 50 patients diagnosed with PA and 10 patients with non-functional adrenal adenoma (NFA). All patients underwent 68Ga-pentixafor PET/CT before adrenalectomy. Immunohistochemistry (IHC) was performed to detect the protein expression of CYP11B2 and the G-protein-coupled receptor CXCR4. RESULTS: CYP11B2 IHC revealed the presence of 43 functional nodules. Subsequently, 40/43 functional nodules could be detected on 68Ga-pentixafor PET/CT, while negative imaging findings were noted for 11/13 non-functional nodules (sensitivity, 93.0%; specificity, 84.6%). The optimum SUVmax cut-off for the identification of functional nodules was 8.95 (AUC 0.914 [0.828-1.000], p < 0.001). Regarding the size of functional nodules, diagnostic efficiency appeared to be much higher for nodules greater than 1 cm in size (sensitivity, up to 97.3%). Moreover, we examined the relationship between CXCR4 and CYP11B2 expression in 56 lesions. All 43 CYP11B2-positive nodules were CXCR4-positive, but one of the 13 CYP11B2-negative nodules (7.7%) showed false-positive staining for CXCR4. Moreover, the consistency between PET/CT uptake and CXCR4 staining results was 92.9% (52/56). CONCLUSIONS: At least 90% of functional nodules show positive uptake on 68Ga-pentixafor PET/CT, and the detection ability is much better for nodules with a diameter ≥ 1 cm. With its high sensitivity and specificity, 68Ga-pentixafor PET/CT can be considered a promising surgical decision-making tool for patients with PA. KEY POINTS: • 68Ga-pentixafor PET/CT could be a useful tool for the identification of functional adrenal nodules in APAs and even IHAs. • The diagnostic efficiency appears to be much higher for nodules ≥ 1 cm in size. • There is high consistency between the results of 68Ga-pentixafor PET/CT imaging and CXCR4 immunohistochemistry.

Imaging findings and clinical relevance of 68Ga-Pentixafor PET in atherosclerosis: a systematic review.

OBJECTIVE: We aimed to perform a qualitative synthesis of evidence on the role of 68Ga-Pentixafor PET in atherosclerosis. METHODS: A systematic search of the PubMed and Embase databases for studies reporting the evaluation of atherosclerotic lesions by 68Ga-Pentixafor PET was performed with a search time frame from database creation to 2022-12-26. The diagnostic test evaluation tool QUADAS-2 was used to evaluate the quality of the included literature and to perform descriptive analyses of relevant outcome indicators. RESULTS: A total of 6 studies with 280 patients were included. One study reported only imaging outcome metrics, while the other five studies reported imaging outcome metrics and clinical correlation metrics. For imaging outcomes, three studies reported imaging results for 68Ga-Pentixafor PET only, and the other three studies reported imaging results for comparative analysis of 68Ga-Pentixafor PET with 18F-FDG PET. For clinical correlation, three studies reported the correlation between tracer uptake and cardiovascular risk factors, one study reported the correlation between tracer uptake and plaque calcification, and one study reported the correlation between all three: tracer uptake, cardiovascular risk factors, and plaque calcification. CONCLUSION: 68Ga-Pentixafor PET has a good imaging effect on atherosclerotic lesions, and it is a promising imaging modality that may replace 18F-FDG PET for atherosclerosis imaging in the future. In patients with atherosclerosis, there is a clear clinical correlation between cardiovascular risk factors, tracer uptake, and plaque calcification.

CXCR4-targeted theranostics in oncology.

A growing body of literature reports on the upregulation of C-X-C motif chemokine receptor 4 (CXCR4) in a variety of cancer entities, rendering this receptor as suitable target for molecular imaging and endoradiotherapy in a theranostic setting. For instance, the CXCR4-targeting positron emission tomography (PET) agent [68 Ga]PentixaFor has been proven useful for a comprehensive assessment of the current status quo of solid tumors, including adrenocortical carcinoma or small-cell lung cancer. In addition, [68 Ga]PentixaFor has also provided an excellent readout for hematological malignancies, such as multiple myeloma, marginal zone lymphoma, or mantle cell lymphoma. PET-based quantification of the CXCR4 capacities in vivo allows for selecting candidates that would be suitable for treatment using the theranostic equivalent [177Lu]/[90Y]PentixaTher. This CXCR4-directed theranostic concept has been used as a conditioning regimen prior to hematopoietic stem cell transplantation and to achieve sufficient anti-lymphoma/-tumor activity in particular for malignant tissues that are highly sensitive to radiation, such as the hematological system. Increasing the safety margin, pretherapeutic dosimetry is routinely performed to determine the optimal activity to enhance therapeutic efficacy and to reduce off-target adverse events. The present review will provide an overview of current applications for CXCR4-directed molecular imaging and will introduce the CXCR4-targeted theranostic concept for advanced hematological malignancies.

Imaging CXCR4 expression in patients with suspected primary hyperaldosteronism.

PURPOSE: It is challenging to differentiate unilateral aldosterone-producing adenoma (APA) from bilateral idiopathic adrenal hyperplasia (IAH) and nonfunctional adrenal adenoma (NFA) in primary aldosteronism (PA). In a first primarily ex vivo study detection, CXC chemokine receptor type 4 (CXCR4) expression has been shown to be a valuable tool for the detection of APA. In this study, we aimed to clinically evaluate CXCR4 imaging with 68Ga-pentixafor PET/CT for detecting APA. METHODS: We prospectively recruited 36 patients with clinical suspicion of PA. All patients underwent 68Ga-pentixafor PET/CT. Positive lesions were defined based on higher tracer uptake in adrenal nodular(s) shown on CT than the normal adrenal. These lesions were referred for adrenalectomy subsequently. All patients received clinical follow-up. Semi-quantitative analysis using maximum standardized uptake value (SUVmax), lesion-to-liver ratio (LLR), and lesion-to-contralateral ratio (LCR) has also been performed. PET/CT results were correlated with clinical presentation and follow-up. RESULTS: Thirty-nine adrenal lesions in 36 patients were found; 25 APA, 4 IAH, and 10 NFA according to histopathology and clinical assessment. Sensitivity, specificity, and accuracy of 68Ga-pentixafor PET/CT in distinguishing APA by visualization were 100%, 78.6%, and 92.3% respectively. The SUVmax of APA (21.34 ± 9.41, n = 25) was significantly higher than that of non-APA lesions (6.29 ± 2.10, n = 14, P < 0.0001). An optimal threshold of SUVmax = 11.18 was determined for predicting APA with a sensitivity of 88.0%, specificity of 100%, and an accuracy of 92.3%. A cutoff value for LCR of 2.12 yielded a sensitivity of 100% and a specificity of 92.9%, whereas a cutoff value for LLR of 2.36 reached at both 100% of sensitivity and specificity. All patients with (removed) positive lesions benefited from surgery. CONCLUSION: 68Ga-Pentixafor PET/CT may be used to non-invasively detect APA in PA patients.

Chemokine receptor-4 targeted PET/CT with 68Ga-Pentixafor in assessment of newly diagnosed multiple myeloma: comparison to 18F-FDG PET/CT.

PURPOSE: 18F-FDG PET/CT has some limitations in the evaluation of multiple myeloma (MM). Since chemokine receptor-4 is overexpressed in MM, we perform a prospective cohort study to compare the performance of 68Ga-Pentixafor and 18F-FDG PET/CT in newly diagnosed MM. METHODS: Thirty patients with newly diagnosed MM were recruited. All patients underwent 68Ga-Pentixafor and18F-FDG PET/CT within 1 week after enrollment. A positive PET/CT was defined as the presence of focal PET-positive lesions in bone marrow or diffuse bone marrow patterns (uptake > liver). Bone marrow uptake values in 68Ga-Pentixafor and18F-FDG PET/CT (total bone marrow glycolysis [TBmGFDG], total bone marrow uptake with 68Ga-Pentixafor [TBmUCXCR4], total bone marrow volume [TBmV], SUVmean, and SUVmax) were obtained by drawing total bone marrow volume of interest on PET/CT. The positive rates of the PET/CT scans were statistically compared, and the correlation between quantitative bone marrow uptake values and clinical characteristics, laboratory findings, and staging was analyzed. RESULTS: 68Ga-Pentixafor PET/CT had a higher positive rate than 18F-FDG PET/CT in recruited patients (93.3 vs. 53.3%, p = 0.0005). In quantitative analysis, bone marrow uptake values in 68Ga-Pentixafor (TBmUCXCR4, SUVmax, and SUVmean) were positively correlated with end organ damage, staging, and laboratory biomarkers related to tumor burden including serum ß2-microglobulin, serum free light chain, and 24-h urine light chain (p < 0.05). In 18F-FDG PET/CT, only the SUVmean of total bone marrow was positively correlated with serum free light chain and 24-h urine light chain (p < 0.05). CONCLUSIONS: 68Ga-Pentixafor PET/CT is promising in assessment of newly diagnosed MM. TRIAL REGISTRATION NUMBER: NCT03436342.

[68Ga]Pentixafor PET/MR imaging of chemokine receptor 4 expression in the human carotid artery.

PURPOSE: Type 4 chemokine receptor (CXCR4) plays an important role in immune cell migration during the atherosclerosis progression. We aimed to evaluate [68Ga]Pentixafor positron emission tomography (PET) in combination magnetic resonance imaging (MRI) for in vivo quantification of CXCR4 expression in carotid plaques. METHODS: Seventy-two patients with lymphoma were prospectively scheduled for whole body [68Ga]Pentixafor PET/MRI with an additional T2-weighted carotid sequence. Volumes of interest (VOIs) were drawn along the carotid bifurcation regions, and the maximum tissue-to-blood ratios (TBR) of [68Ga]Pentixafor uptake were calculated. Lesions were categorized into non-eccentric (n = 27), mild eccentric (n = 67), moderately (n = 41) and severely (n = 19) eccentric carotid atherosclerosis. A different cohort of symptomatic patients (n = 10) with carotid stenosis scheduled for thrombendarterectomy (TEA) was separately imaged with 3T MRI with dedicated plaque sequences (time of flight, T1-, and T2-weighted). MRI findings were correlated with histochemical assessment of intact carotid plaques. RESULTS: At hybrid PET/MRI, we observed significantly increased [68Ga]Pentixafor uptake in mildly (mean TBRmax = 1.57 ± 0.27, mean SUVmax = 2.51 ± 0.39), moderately (mean TBRmax = 1.64 ± 0.37, mean SUVmax = 2.61 ± 0.55) and severely eccentric carotids (mean TBRmax = 1.55 ± 0.26, mean SUVmax = 2.40 ± 0.44) as compared to non-eccentric carotids (mean TBRmax = 1.29 ± 0.21, mean SUVmax = 1.77 ± 0.42) (p ≤ 0.05). Histological findings from TEA confirmed that prominent CXCR4 expression was localized within inflamed atheromas and preatheromas. Co-localization of cellular CXCR4 and CD68 expression in the plaque was observed by immunofluorescence staining. CONCLUSIONS: In vivo evaluation of CXCR4 expression in carotid atherosclerotic lesions is feasible using [68Ga]Pentixafor PET/MRI. In atherosclerotic plaque tissue, CXCR4 expression might be used as a surrogate marker for inflammatory atherosclerosis.

[68Ga]Pentixafor-PET/MRI for the detection of Chemokine receptor 4 expression in atherosclerotic plaques.

PURPOSE: The expression of chemokine receptor type 4 (CXCR4) was found co-localized with macrophages on the atherosclerotic vessel wall and participated in the initial emigration of leukocytes. Gallium-68 [68Ga]Pentixafor has recently been introduced for the imaging of atherosclerosis by targeting CXCR4. We sought to evaluate human atherosclerotic lesions using [68Ga]Pentixafor PET/MRI. METHODS: Thirty-eight oncology patients underwent [68Ga]Pentixafor PET/MR imaging at baseline. Maximum standardized uptake values (SUVmax) were derived from hot lesions in seven arterial segments and target-to-blood ratios (TBR) were calculated. ANOVA post-hoc and paired t test were performed for statistical comparison, Spearman's correlation coefficient between uptake ratios and cardiovascular risk factors were assessed. The reproducibility of [68Ga]Pentixafor PET/MRI was assessed in seven patients with a follow-up exanimation by Pearson's regression and Bland-Altman plots analysis. RESULTS: Thirty-four of 38 patients showed 611 focal [68Ga]Pentixafor uptake that followed the contours of the large arteries. Both prevalence and mean TBRmax were highest in the descending aorta. There were significantly higher TBR values found in men (1.9 ± 0.3) as compared to women (1.7 ± 0.2; p < 0.05). Patients with mean TBRmax > 1.7 showed a significantly higher incidence of diabetes, hypertension hypercholesterolemia and history of cardiovascular disease than patients with mean TBRmax ≤ 1.7. [68Ga]Pentixafor uptake showed a good reproducibility (r = 0.6, p < 0.01), and there was no difference between the mean TBRmax values of plaque lesions (TBRbaseline1.8 ± 0.3 vs TBRfollow-up1.8 ± 0.3) (p = 0.9). CONCLUSION: Patients with high arterial uptake showed increased incidence of cardiovascular risk factors, suggesting a potential role of [68Ga]Pentixafor in characterization of atherosclerosis.

A comparison of the performance of 68Ga-Pentixafor PET/CT versus adrenal vein sampling for subtype diagnosis in primary aldosteronism.

Objective: To investigate the diagnostic efficiency and prognostic value of 68Ga-Pentixafor PET/CT in comparison with adrenal vein sampling (AVS) for functional lateralization in primary aldosteronism (PA). Histology and long-term clinical follow-up normally serve as the gold standard for such diagnosis. Methods: We prospectively recruited 26 patients diagnosed with PA. All patients underwent 68Ga-Pentixafor PET/CT and AVS. Postsurgical biochemical and clinical outcomes of patients with unilateral primary aldosteronism (UPA), as diagnosed by PET/CT or AVS, were assessed by applying standardized Primary Aldosteronism Surgical Outcome (PASO) criteria. Immunohistochemistry (IHC) was performed to detect the expression of aldosterone synthase (CYP11B2) and CXCR4. Results: On total, 19 patients were diagnosed with UPA; of these, 13 patients were lateralized by both PET/CT and AVS, four patients were lateralized by PET-only, and two by AVS-only. Seven subjects with no lateralization on AVS and PET received medical therapy. All patients achieved complete biochemical success except one with nodular hyperplasia lateralized by AVS alone. The consistency between PET/CT and AVS outcomes was 77% (20/26). Moreover, CYP11B2-positive nodules were all CXCR4-positive and showed positive findings on PET. Patients who achieved complete biochemical and clinical success had a higher uptake on PET as well as stronger expression levels of CXCR4 and CYP11B2. Conclusion: Our analysis showed that 68Ga-Pentixafor PET/CT could enable non-invasive diagnosis in most patients with PA and identify additional cases of unilateral and surgically curable PA which could not be classified by AVS. 68Ga-Pentixafor PET/CT should be considered as a first-line test for the future classification of PA.

68Ga-DOTATATE and 68Ga-Pentixafor PET/CT in a Patient with Castleman Disease of the Retroperitoneum.

This is a case of a 42-year-old man with recurrent symptoms of dizziness and a newly found retroperitoneal mass with no 131I-MIBG uptake who was referred for restaging with 68Ga-DOTATATE PET/CT and local 68Ga-pentixafor PET/CT. The examinations both showed intense radioactivity uptake in the retroperitoneal mass and no abnormal uptake in the right adrenal nodule. Two lesions showed distinct properties of radioactivity uptake, which suggested the possibility of different sources. A postoperative pathological test revealed that the morphology and immunohistochemistry of the retroperitoneal mass was found to be consistent with Castleman disease, and the right adrenal gland was normal tissue.

Prospective Phase II Study of Radiotherapy Dose Escalation in Grade 4 Glioma Using 68Ga-Pentixafor PET Scan.

AIMS: Local failure remains the major concern in grade 4 glioma or glioblastoma (GBM). Pilot studies have shown a radiotherapy (RT) dose-response relationship in GBM. Here we present our preliminary data of RT dose escalation using 68Ga-Pentixafor PET scan. High 68Ga-pentixafor uptake in glioma cells helps in sharp demarcation between tumour and normal brain. MATERIALS AND METHODS: This phase II prospective study was conducted from 2018 to 2020. Thirty, biopsy-proven cases of grade 4 glioma were included. All patients underwent post-operative MRI of the brain and 68Ga-Pentixafor PET scan. RT was planned in 2-phases. Phase-1 GTV (GTV1) comprised of T2/flair abnormality, PET-avid disease and post-op cavity. A margin of 2cm was given to GTV-1 to create phase-1 CTV (CTV1), which was further expanded to 0.5cm to generate phase-1 PTV (PTV1). A radiation dose of 46Gy/23fr was prescribed to PTV-1. Phase-2 GTV (GTV2) consisted of CT/MRI contrast-enhancing lesion, PET avid disease and post-op cavity. A margin of 0.5 cm was given to GTV2 to create phase-2 CTV (CTV2) which was expanded to 0.5 cm to create phase-2 PTV (PTV2). RT dose of 14 Gy/7 fr was prescribed to PTV2. PET avid disease was delineated as GTV PET and a margin of 3mm was given to generate PTV-PET which received escalated RT dose of 21 Gy/7fr by simultaneous integrated boost (SIB) in phase 2 (Total dose to PTV PET = 67 Gy/30 fr). All patients received concurrent and adjuvant temozolomide. The data was prospectively maintained in Microsoft Excel sheet. SPSS v 23 was used for statistical analysis. The primary endpoints were estimation of the overall survival (OS) and progression-free survival (PFS), and secondary endpoint was to measure the incidence of radiation necrosis. Categorical variables were reported as frequency and percentage and quantitative variables were reported as median and range. RESULTS: Data from thirty patients were analysed. A median OS of 23 months was observed with estimated 1, 2 and 3 years OS of 90%, 40% and 17.8% respectively. A significant association of OS was seen with the extent of surgery (p = 0.04) and kernofsky performance status (p = 0.007). No patient developed significant radiation necrosis. CONCLUSIONS: The index study did not show any survival benefit from dose escalation RT. However, all of the patients tolerated the treatment well and none of them developed radiation necrosis. Considering the small sample size as a limitation of the index study, the role of 68Ga-pentixafor PET scan for radiation dose escalation should be further explored. CLINICAL TRIAL NUMBER: CTRI/2019/05/019146.

Clinical value of 68Ga-pentixafor PET/CT in patients with primary aldosteronism and bilateral lesions: preliminary results of a single-centre study.

BACKGROUND: Subtype diagnosis of primary aldosteronism (PA) is used to determine treatment, and the potential utility of 68Ga-pentixafor PET/CT for investigation of PA has long been recognized. The study aimed to evaluate the clinical value of 68Ga-pentixafor PET/CT in the diagnosis and prognosis of patients with bilateral lesions identified by CT. METHODS: In total, 25 patients with PA and bilateral lesions on CT were retrospectively evaluated. All patients underwent 68Ga-Pentixafor PET/CT and adrenal vein sampling. The analysis focused on establishing the relationship between bilateral adrenal lesions SUVmax and the ratio of bilateral adrenal lesions SUVmax (CON) and clinical diagnosis, treatment outcomes, and KCNJ5 gene status. RESULTS: The concordance rate between 68Ga-Pentixafor PET/CT and adrenal venous sampling was 65.2% (15/23). The lateralization results of 68Ga-pentixafor PET/CT supported the clinical decisions of 20 patients with PA, 90% of whom showed effectiveness in treatment. The SUVmax on the dominant side of the surgically treated patients was higher than that of patients treated with drugs. The SUVmax of the KCNJ5 mutant group was higher than that of the KCNJ5 wild group, and 68Ga-Pentixafor uptake was correlated with KCNJ5 gene status. CONCLUSIONS: 68Ga-Pentixafor PET/CT proves beneficial for patients with PA with bilateral lesions on CT. The treatment is generally effective based on the results of PET lateralization. Simultaneously, a certain relationship exists between 68Ga-Pentixafor PET/CT and KCNJ5 gene status, warranting further analysis.

Comparison of [18F]FDG and [68 Ga]pentixafor PET/CT in Nasopharyngeal Carcinoma.

PURPOSE: This study aimed to explore the feasibility of [68 Ga]pentixafor positron emission tomography/computed tomography (PET/CT) in patients with nasopharyngeal carcinoma (NPC). PROCEDURES: This prospective study included patients with NPC who underwent [68 Ga]pentixafor PET/CT and 2-[18F]fuoro-2-deoxy-D-glucose ([18F]FDG) PET/CT within one week between November 2022 and March 2023. The [68 Ga]pentixafor and [18F]FDG uptakes in primary and metastatic lesions were measured and compared. RESULTS: Twenty-five participants (21 patients for initial stage and four patients for recurrence detection) were enrolled in our study. The participants underwent [18F]FDG PET/CT and [68 Ga]pentixafor PET/CT. [68 Ga]pentixafor PET/CT had the same detection rate as [18F]FDG for primary tumor (96% vs. 96%). The [68 Ga]pentixafor maximum standard uptake value (SUVmax) and target-to-background ratio (TBR) of primary tumors were lower than those of [18F]FDG (SUVmax: 8.13 ± 2.78 vs. 14.25 ± 6.45; P < 0.01; TBR: 5.17 ± 2.14 vs. 9.81 ± 5.30, P < 0.01). The difference between tumor volume of [68 Ga]pentixafor (TVpentixafor) and tumor volume of [18F]FDG (TVFDG) showed no significance (median: 16.01 vs. 9.56, P = 0.332). In the detection of suspected metastatic cervical lymph nodes (CLNs), [68 Ga]pentixafor PET possessed a lower SUVmax than [18F]FDG PET/CT (SUVmax: 6.86 ± 2.63 vs. 10.39 ± 5.28, P < 0.01), but there was no significant difference in the detection rate between [68 Ga]pentixafor and [18F]FDG PET/CT (96 vs. 98, P = 0.613). CONCLUSIONS: [68 Ga]pentixafor is a promising imaging tracer for detecting primary and metastatic NPC. [68 Ga]pentixafor PET/CT is comparable to [18F]FDG PET/CT in the detection rate of primary tumors and metastatic cervical lymph nodes in nasopharyngeal carcinoma, but [68 Ga]pentixafor uptake was heterogeneous. [68 Ga]pentixafor PET/CT may help select patients most likely to benefit from CXCR4-directed endoradiotherapy. CLINICAL TRIAL REGISTRATION NO: ChiCTR2200065902.

68Ga-pentixafor PET/CT in the localization diagnosis of primary aldosteronism concurrent subclinical cushing's syndrsome: two case reports.

PURPOSE: Adrenal venous sampling (AVS) is recommended for subtyping primary aldosteronism (PA). However, in cases of PA, concurrent subclinical Cushing's syndrome (SCS) has the potential to confound AVS results. Pentixafor, a CXC chemokine receptor type 4-specific ligand, has been reported as a promising marker to evaluate functional nature of adrenal adenomas. This study aims to investigate the clinical value of Gallium-68 Pentixafor Positron Emission Tomography-Computed Tomography (68Ga-Pentixafor PET/CT) in the localization diagnosis of patients with PA plus SCS. METHODS: Two patients with a confirmed diagnosis of PA plus SCS underwent AVS and 68Ga-Pentixafor PET/CT. RESULTS: AVS results revealed no lateralization for both patients while 68Ga-Pentixafor PET/CT showed a unilateral adrenal nodule with increased uptake of 68Ga-Pentixafor. Unilateral adrenalectomy was performed based on the results of 68Ga-Pentixafor PET/CT. Subsequently, complete biochemical remission of autonomous aldosterone and cortisol secretion were achieved in both cases. CONCLUSIONS: 68Ga-Pentixafor PET/CT shows promising potential for the localization of aldosterone and cortisol co-secreting adrenal adenoma in patients with PA plus SCS.

68Ga-Pentixafor PET/CT May Fail to Detect Recurrent Multiple Myeloma with Extramedullary Disease.

Two patients with a history of multiple myeloma experienced a recurrence of the disease.18F-FDG PET/CT revealed prominent extramedullary disease as well as multi-foci in the bone marrow, both with increased FDG uptake. However, on 68Ga-Pentixafor PET/CT, all the myeloma lesions showed significantly lower tracer uptake in comparison with 18F-FDG PET. This false-negative result of recurrent multiple myeloma with extramedullary disease may be a potential limitation of 68Ga-Pentixafor in assessing multiple myeloma.

Bing-Neel Syndrome and Coexisting Pituitary Macroadenoma in a Patient with Waldenström Macroglobulinemia Revealed by 18F-FDG and 68Ga-Pentixafor PET/CT.

A 63-year-old man presenting with peripheral neuropathies was diagnosed of Waldenström's macroglobulinemia, and Bing-Neel syndrome was subsequently confirmed via cerebrospinal fluid examinations. Besides involvement in bone marrow, lymph nodes, as well as the thoracic and sacral nerve root, 68Ga-Pentixafor PET/CT detected active tracer uptake in bilateral choroid plexus, which was negative in 18F-FDG PET/CT, possibly suggesting the involvement of Bing-Neel syndrome. The coexisting pituitary macroadenoma was FDG-avid but negative in 68Ga-Pentixafor PET/CT. After six cycles of chemotherapy, the follow-up PET/CT showed complete remission of the previous disease, including the high uptake of 68Ga-Pentixafor in choroid plexus. However, the hypermetabolic pituitary macroadenoma remained unchanged.

The Value of Targeting CXCR4 With 68Ga-Pentixafor PET/CT for Subtyping Primary Aldosteronism.

CONTEXT: Primary aldosteronism (PA) is one of the leading causes of secondary hypertension, and its diagnostic subtyping consistently presents a clinical challenge. OBJECTIVE: This study aimed to investigate the potential of 68Ga-Pentixafor positron emission tomography/computed tomography (PET/CT) in PA classification and its applicability in guiding the development of clinical treatment plans by increasing the sample size. METHODS: We prospectively enrolled 120 patients with either PA or nonfunctional adenoma (NFA) for analysis. All patients underwent 68Ga-Pentixafor PET/CT. Of these, 11 patients underwent adrenal venous sampling (AVS), 77 underwent adrenalectomy, 76 received pathological diagnoses, and 71 underwent immunohistochemical detection of aldosterone synthase (CYP11B2). Immunohistochemistry for C-X-C chemokine receptor 4 (CXCR4) was performed in 62 cases. Follow-up was conducted for all patients. RESULTS: Among the 120 patients, 66 were diagnosed with aldosterone-producing adenoma (APA), 33 with idiopathic hyperaldosteronism (IHA), and 21 with NFA. For APA patients, the sensitivity, specificity, and accuracy of visual analysis using 68Ga-Pentixafor PET/CT were 92.40%, 94.40%, and 93.33%, respectively. Furthermore, for APA patients with a nodule greater than 1 cm in diameter, when the maximum standard uptake value was 7.3 or greater, the specificity was 100%; and for APA patients with a nodule less than 1 cm in diameter, 68Ga-Pentixafor PET/CT also exhibited high sensitivity. AVS was successfully performed in 5 patients. Among the 5 patients, the concordance rate between the AVS and 68Ga-Pentixafor PET/CT for PA subtyping was 60%. In the 77 patients who underwent adrenalectomy, 61 PET/CT scans displayed positive lesions, all of which benefited from the surgery. Additionally, the concordance rate between 68Ga-Pentixafor PET/CT imaging and CYP11B2 was 81.69%. CONCLUSION: 68Ga-Pentixafor PET/CT is a reliable and noninvasive functional imaging technique that demonstrates high accuracy in classifying PA and provides valuable guidance for clinical treatment decision-making.

New Developments in Myeloma Treatment and Response Assessment.

Recent innovative strategies have dramatically redefined the therapeutic landscape for treating multiple myeloma patients. In particular, the development and application of immunotherapy and high-dose therapy have demonstrated high response rates and have prolonged remission duration. Over the past decade, new morphologic or hybrid imaging techniques have gradually replaced conventional skeletal surveys. PET/CT using 18F-FDG is a powerful imaging tool for the workup at diagnosis and for therapeutic evaluation allowing medullary and extramedullary assessment. The independent negative prognostic value for progression-free and overall survival derived from baseline PET-derived parameters such as the presence of extramedullary disease or paramedullary disease, as well as the number of focal bone lesions and SUVmax, has been reported in several large prospective studies. During therapeutic evaluation, 18F-FDG PET/CT is considered the reference imaging technique because it can be performed much earlier than MRI, which lacks specificity. Persistence of significant abnormal 18F-FDG uptake after therapy is an independent negative prognostic factor, and 18F-FDG PET/CT and medullary flow cytometry are complementary tools for detecting minimal residual disease before maintenance therapy. The definition of a PET metabolic complete response has recently been standardized and the interpretation criteria harmonized. The development of advanced PET analysis and radiomics using machine learning, as well as hybrid imaging with PET/MRI, offers new perspectives for multiple myeloma imaging. Most recently, innovative radiopharmaceuticals such as C-X-C chemokine receptor type 4-targeted small molecules and anti-CD38 radiolabeled antibodies have shown promising results for tumor phenotype imaging and as potential theranostics.

Imaging Inflammation in Atherosclerosis with CXCR4-Directed [68Ga]PentixaFor PET/MRI-Compared with [18F]FDG PET/MRI.

(1) This study compared [68Ga]PentixaFor uptake in active arterial segments with corresponding [18F]FDG arterial uptake as well as the relationship with cardiac [68Ga]PentixaFor uptake. (2) Method: Tracer uptake on atherosclerotic lesions in the large arteries was measured and target-to-background ratios (TBR) were calculated to adjust background signals with two investigators blinded to the other PET scan. On a patient-based and lesion-to-lesion analysis, TBR values of two tracers were compared and the relationship with cardiac inflammation was further explored. Furthermore, two cardiovascular risk-related groups were divided to explore the value of risk stratification of the two tracers in atherosclerosis. (3) Results: [68Ga]PentixaFor PET/MRI identified more lesions (88% vs. 48%; p < 0.001) and showed higher uptake than [18F]FDG PET/MRI (TBR, 1.90 ± 0.36 vs. 1.63 ± 0.29; p < 0.001). In the patient-based analysis, the TBR of [68Ga]PentixaFor uptake was also significantly higher than [18F]FDG uptake (1.85 ± 0.20 vs. 1.42 ± 0.19; p < 0.001). The TBR of active lesions for [68Ga]PentixaFor was significantly increased in the high-risk group (n = 9), as compared to the low-risk group (n = 10) (2.02 ± 0.15 vs. 1.86 ± 0.10, p = 0.015), but not for [18F]FDG (1.85 ± 0.10 vs. 1.80 ± 0.07, p = 0.149). (4) Conclusion: [68Ga]PentixaFor PET/MRI identified many more lesions than [18F]FDG PET/MRI. Patients with high-risk cardiovascular factors illustrated an increased uptake of [68Ga]PentixaFor. There was a correlation between the elevated uptake of [68Ga]PentixaFor in the active arterial segments and heart.

68Ga-Pentixafor PET/CT Demonstrating In Vivo CXCR4 Receptor Overexpression in Rare Lung Malignancies: Correlation with Histologic and Histochemical Findings.

68Ga-pentixafor PET/CT imaging allows noninvasive assessment of C-X-C chemokine receptor type 4 (CXCR4) expression in various malignancies, but its use in rare lung cancer variants has not been reported. Methods: 68Ga-pentixafor PET/CT imaging was performed on 6 patients (3 men, 3 women; mean age, 57.0 ± 16.8 y) with suspected lung masses. Whole-body PET/CT images were acquired 1 h after intravenous injection of 148.0-185.0 MBq of the tracer. PET/CT images were reconstructed and analyzed. The image findings were correlated with histopathologic and quantitative (CXCR4) fluorescence-activated cell sorting analysis. Results: Histopathologic diagnosis of hemangioendothelioma, sarcomatoid carcinoma, and hemangiopericytoma was confirmed in 1 patient each. Lung metastasis was diagnosed in the remaining 3 of 6 patients with primary sarcoma (n = 1), renal cell carcinoma (n = 1), and unknown primary (n = 1). Increased uptake in the primary lung mass, with an SUVmax of 3.0, 6.34, and 13.0, was noted in the hemangiopericytoma, sarcomatoid carcinoma and hemangioendothelioma cases, respectively. The mean SUVmax, mean fluorescence intensity, and percentage of stained cells were highest in hemangioendothelioma. Among 3 patients with lung metastases, the highest SUVmax, 9.5, was in the primary sarcoma patient. Conclusion: 68Ga-pentixafor selectively targets the in vivo whole-body disease burden of CXCR4 receptors. This approach thus holds promise for developing suitable radiotheranostics for lung cancers expressing these targets.